Glucose, one of the most important energy sources for body, is taken up into a cell across cell membrane to be made available in the body. A membrane protein called glucose transporter is involved in this uptake at cell membrane. Glucose transporter is classified into two main categories of facilitated glucose transporter which uptakes glucose depending on intracellular and extracellular glucose concentration difference, and sodium/glucose cotransporter (SGLT) which uptakes glucose by using intracellular and extracellular ion concentration difference (for example, see the following Reference 1). Regarding SGLT, it has been known that SGLT1, sodium/glucose cotransporter having a high affinity, mainly exists in the small intestine, and SGLT2, sodium/glucose cotransporter having a low affinity, mainly exists in renal tubule (for example, see the following References 2 and 3). In addition, SGLT3, a human homologue of pig sodium/glucose cotransporter with a low affinity, pSAAT (for example, see the following Reference 4) was reported (for example, see the following Reference 5). Thus, SGLTs are involved in glucose absorption in the small intestine and glucose reabsorption in the kidney (for example, see the following Reference 6). Therefore, a SGLT inhibitor is expected to lower blood glucose level by suppressing the intestinal glucose absorption and accelerating glucose excretion into urine. Actually, as a result of a study using phlorizin known as a SGLT inhibitor, it was confirmed that by inhibiting SGLT urinary glucose excretion increased, blood glucose level lowered and insulin resistance was improved (for example, see the following References 7 and 8). In these years, various SGLT inhibitors has been found and are currently under development as treatment agents for diseases associated with glucose, lipid and energy metabolism including diabetes (for example, see the following References 9-12).
In these years, a gene that codes for a protein having a sodium/glucose cotransporting activity was newly reported (see the following Reference 13) and applied for a patent (Japan Patent Application no.2002-88318). The protein of the Japan patent application no.2002-88318 (hereinafter referred to as SMINT) has 7 amino-acid residues (Met Ser Lys Glu Leu Ala Ala; SEQ ID NO: 1) at N-terminal extended from a protein described in the Reference 13 (hereinafter referred to as SGLTh). The both proteins share high DNA and amino-acid sequence homology with SGLT1 and SGLT2, and mammalian cells being expressed these genes show an activity of the sodium-dependent sugar uptake. Therefore, the both are considered as a member of SGLT family.
Among these SGLTs, SGLT1 is known to transport galactosein addition to glucose (for example, see the following Reference 14), while SGLT2 and SGLT3 have low abilities transporting sugars other than glucose (for example, see the following References 4 and 15). However, the characteristics of SMINT and SGLTh in transporting sugars have not been understood at all.
It has been known that blood mannose level increases in diabetes (for example, see the following Reference 16). In addition, it is known that blood mannose level has a positive correlation with blood glucose level and triglyceride level and a negative correlation with HDL cholesterol in metabolic syndrome (for example, see the following Reference 17). On the other hand, it is known that fructose consumes a lot of ATP through the intracellular metabolic pathway and forms lactose, and that causes a so-called fructose toxicity (for example, see the following Reference 18). Mannose and fructose are known to accumulate in renal glomerulus in diabetic rats, and their relations with diabetic nephropathy have been pointed out (for example, see the following Reference 19). Moreover, it has been reported that mannose and fructose have a protein glycation ability more than 5-times as glucose in glycation reaction with proteins considered as a cause of diabetic complications (for example, see the following Reference 20). Furthermore, it was reported that 1,5-anhydroglucitol/fructose/mannose transporter exists functionally in the kidney, etc. (for example, see the following References 21 and 22). Therefore, as the inhibitory effects on the excess consumption of fructose and mannose as well as glucose in the body are expected to be desirable for the prevention, inhibition of progression or the like of diabetic complications, especially including diabetic nephropathy, it has been desired to early develop an agent having such an inhibitory effect.
Although various compounds having a pyrazole structure like the present invention are known, these compounds are SGLT1 or SGLT2 inhibitors, or SGLT inhibitors which have excreting effects of urinary glucose. Therefore, it has not been known that pyrazole derivatives of the present invention have an inhibitory effect on 1,5-anhydroglucitol/fructose/mannose transporter activity, exert an inhibitory effect on uptake of carbohydrates such as glucose, fructose and mannose, and are useful for the prevention, inhibition of progression or treatment of diseases associated with excess uptake of at least a kind of carbohydrates selected from glucose, fructose and mannose (for example, see the following References 23-31).
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Reference 5: GenBank Data Bank, online, search held on Mar. 11, 2002, Accession No. AJ133127;
Reference 6: Bernard Thorens, Am. J. Physiol., April 1996, Vol. 270, pp. G541-G553;
Reference 7: Luciano Rossetti and 4 persons, J. Clin. Invest., May 1987, Vol. 79, pp. 1510-1515;
Reference 8: Barbara B. Kahn and 4 persons, J. Clin. Invest., February 1991, Vol. 87, pp. 561-570;
Reference 9: International Publication no.WO01/27128;
Reference 10: Kenji Arakawa and 7 persons, Br. J. Pharmacol., January 2001, Vol. 132, No. 2, pp. 578-586;
Reference 11: Masayuki Isaji and 8 persons, FASEB J., March 2001, Vol. 15, No. 4, p.A214;
Reference 12: Kenji Katsuno and 7 persons, FASEB J., March 2001, Vol. 15, No. 4, p.A214;
Reference 13: International Publication no.WO02/053738;
Reference 14: E. Turk and 4 persons, Nature, March 1991, Vol. 350, No. 6316, pp. 354-356;
Reference 15: Yoshikatsu Kanai and 4 persons, J. Clin. Invest., January 1994, Vol. 93, pp. 397-404;
Reference 16: Elja Pitkanen, Clin. Chim. Acta, July 1996, Vol. 251, No. 1, pp. 91-103;
Reference 17: 0. M. Pitkanen and 2 persons, Scand J. Clin. Lab. Invest., December 1999, Vol. 59, No. 8, pp. 607-612;
Reference 18: R. Gitzelmann and 2 persons, The Metabolic and Molecular Bases of Inherited Disease, McGraw-Hill in the US, 1995, pp. 905-934;
Reference 19: Li Ning Wang and 3 persons, The Japanese Journal of Nephrology, 1990, Vol. 32, No. 4, pp. 401-408;
Reference 20: H. Franklin Bunn and 1 person, Science, July 1981, Vol. 213, pp. 222-224;
Reference 21: Toshikazu Yamanouchi and 5 persons, Biochim. Biophys. Acta., August 1996, Vol. 1291, No. 1, pp. 89-95;
Reference 22: T. Blasco and 5 persons, J. Membr. Biol., November 2000, Vol. 178, No. 2, pp. 127-135;
Reference 23: International Publication no.WO01/16147;
Reference 24: International Publication no.WO02/05373;
Reference 25: International Publication no.WO02/068439;
Reference 26: International Publication no.WO02/068440;
Reference 27: International Publication no.WO03/098893;
Reference 28: International Publication no.WO03/020737;
Reference 29: International Publication no.WO02/36602;
Reference 30: International Publication no.WO02/088157;
Reference 31: Japan Patent Publication no.JP2003-12686.